Phenotype prediction for mucopolysaccharidosis type I by in silico analysis

Ou, Li; Przybilla, Michael; Whitley, Chester B.

doi:10.1186/s13023-017-0678-1

Cited by 30 publications

(37 citation statements)

References 34 publications

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“…Even though the crystal structure of IDUA complexed with various substrates has been published, the conformation of the active site defined, and it has been shown that the high mannose glycan at Asn372 contributes to the enzymatic activity, it still remains a challenge to use this structure directly to a priori predict the functional effect of sequence variants on the processing and enzymatic activity of the protein . Most of the recurrent variants reported here have been discussed in relation to in silico structural and functional effects on the IDUA protein and although one can use these various models to explore the effects of variants on protein structure, the real‐life data reported through the Registry is invaluable and arguably more relevant to clinical management decisions.…”

Section: Discussionmentioning

confidence: 99%

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

et al. 2019

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Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α‐L‐iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler‐Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype‐phenotype correlation in large MPS I cohorts have been performed. Understanding genotype‐phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.

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Section: Discussionmentioning

confidence: 99%

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

et al. 2019

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“…SAAMP 2.0 yielded a total sensitivity of 94.9% (95.1% in IDS , 95.1% in IDUA and 94.3% in GLB1 ), and a specificity of 89.7%. Considering the importance of early diagnosis, even a seemingly small increase in sensitivity and specificity represents a significant improvement over the SAAMP 1.0 …”

Section: Resultsmentioning

confidence: 99%

“…A total of 7 bioinformatics tools were used as previously described . These tools include SIFT (http://sift.jcvi.org/), PolyPhen (http://genetics.bwh.harvard.edu/pph2), I‐Mutant (http://gpcr2.biocomp.unibo.it/cgi/predictors/I-Mutant3.0/I-Mutant3.0.cgi), PROVEAN (http://provean.jcvi.org/index.php), PANTHER (http://www.pantherdb.org/), SNPs&GO (http://snps.biofold.org/snps-and-go/snps-and-go.html), PHD‐SNP (http://snps.biofold.org/phd-snp/phd-snp.html).…”

Section: Methodsmentioning

confidence: 99%

“…A TM‐score > 0.5 highlights a model of correct topology, and a TM‐score < 0.17 indicates a random similarity. Further, the Swiss‐PDB viewer and Project Have yOur Protein Explained (HOPE; http://www.cmbi.ru.nl/hope/home) were used for analyzing structural impacts of these mutations as previously described …”

Section: Methodsmentioning

confidence: 99%

“…To this end, we utilized the bioinformatics tools to analyze mutations in the IDUA gene and established a guideline for predicting genotype-phenotype correlation of MPS I disease ( Figure 1). 6 More importantly, a SAAMP algorithm was established to predict the phenotype of amino-acid changes by integrating prediction results of these 7 bioinformatics tools. When tested in the IDUA gene, the SAAMP algorithm yielded a sensitivity of 94% and a specificity of 80%.…”

Section: Introductionmentioning

confidence: 99%

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SAAMP 2.0: An algorithm to predict genotype‐phenotype correlation of lysosomal storage diseases

Ou¹,

Przybilla

Whitley

2018

Clinical Genetics

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Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino-acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAAMP 2.0 was developed by excluding 3 tools with worst performance, yielding a sensitivity of 94% and a specificity of 90%. To generalize the guideline to proteins without known structures, we built the three-dimensional model of iduronate-2-sulfatase by homology modeling. Further, we investigated the phenotype severity of known disease-causing mutations of the GLB1 gene, which lead to 2 LSDs (GM1 gangliosidosis and Morquio disease type B). Based on the previous literature and structural analysis, we associated these mutations with disease subtypes and proposed a theory to explain the complicated genotype-phenotype correlation. Collectively, an updated guideline for phenotype prediction with SAAMP 2.0 was proposed, which will provide essential information for early diagnosis and proper treatment allocation, and they may be generalized to many monogenic diseases.

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Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Taghikhani

Khatami

Abdi

et al. 2019

Clinical Laboratory Analysis

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BackgroundMucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by a deficiency of α‐l‐iduronidase (IDUA) encoded by the IDUA gene. We examined the mutation spectrum of the IDUA gene to explain the clinical, biochemical, and molecular features in 21 Iranian patients with MPSI.MethodsSanger sequencing was used to measure the IDUA gene sequence in the coding region and exon‐intron boundaries. We recorded the clinical findings of studied patients at the first diagnosis of disease and then during the treatment and follow‐up.ResultsFive different missense disease‐causing mutations were determined in our patient groups, indicating 90.48% of detection rate. The most widespread mutation was the p.Y109H, occurring in 15.625% of all alleles, which was reported for the first time in our study. Other frequent mutations were as follows: p.Ser157Pro (12.5%), p.Gly84Arg (12.5%), p.Asp257His (9.375%), and p.Asp301Glu (9.375%). Three ones of them were new missense mutations: p.Ser157Pro, p.Asp257His, and p.Asp301Glu.DiscussionThe results of this study explain the different spectrum of IDUA gene mutations in our patients with MPSI. We introduced here 32 different variants including four new variants: p.Y109H (15.625%), p.S157P (12.5%), p.D257H (9.375%), and p.D301E (9.375%). In this series, there was no relationship between the happening of clinical features and genotype variations and biochemical findings.

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Phenotype prediction for mucopolysaccharidosis type I by in silico analysis

Cited by 30 publications

References 34 publications

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

SAAMP 2.0: An algorithm to predict genotype‐phenotype correlation of lysosomal storage diseases

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

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